Intradermally administered yellow fever vaccine at reduced dose induces a protective immune response: a randomized controlled non-inferiority trial

Abstract

Background: Implementation of yellow fever vaccination is currently hampered by limited supply of vaccine. An alternative route of administration with reduced amounts of vaccine but without loss of vaccine efficacy would boost vaccination programmes.

Methods and findings: A randomized, controlled, non-inferiority trial was conducted in a Dutch university center between August 2005 and February 2007. A total of 155 primary vaccinated and 20 previously vaccinated volunteers participated. Participants were randomly assigned in a 1ratio1 ratio to receive intradermal (i.d.) vaccination with live attenuated yellow fever 17D vaccine at a reduced dose (1/5(th); 0.1 mL) or the conventional subcutaneous (s.c.) vaccination (0.5 mL). Antibody neutralization titers were determined at 2, 4 and 8 weeks and 1 year after vaccination by counting the reduction in virus-induced plaques in the presence of serial serum dilutions. Adverse events were documented in a 3-week dairy. Viraemia was measured 5 days after vaccination. From 2 weeks up to one year after vaccination, the maximum serum-dilution at which 80% of the virus plaques were neutralized, which indicates protection against yellow fever, did not differ between those given a reduced i.d. dose or standard s.c. dose of vaccine. In all cases the WHO standard of seroprotection (i.e. 80% virus neutralization) was reached (in 77/77 and 78/78, respectively). Similar results were found in the previously vaccinated individuals. Viraemia was detected in half of the primary vaccinated participants, which was not predictive of serological response. In revaccinees no viraemia was detected.

Conclusions: Intradermal administration of one fifth of the amount of yellow fever vaccine administered subcutaneously results in protective seroimmunity in all volunteers. Albeit this vaccination route should enable vaccination of five-times as many individuals at risk for disease, these results should now be confirmed in field studies in areas with potential yellow fever virus transmission to change vaccination policy.

Trial registration: Nederlands Trial Register ISRCTN46326316.

Figure 1. Flow chart of study participants.

Included study participants from August 2005 until February 2007. PV = post vaccination. RT−PCR = Reverse transcriptase polymerase chain reaction. Wks = weeks and yr = year.

Figure 2. Protective virus neutralization after intradermal or subcutaneous vaccination against yellow fever.

Comparison of reciprocal serum dilutions at which 80% of yellow fever virus is neutralized in constant virus – varying serum dilution test after intradermal and subcutaneous YF vaccination in primary vaccinated participants (n = 155). Bars represent 95% Confidence Intervals (CI). Virus neutralizing capacity of serum in both groups was performed at similar time points but indicators are juxtaposed for visual enhancement. VN = virus neutralization.

Figure 3. Pre- and post vaccination virus neutralizing capacity of serum of previously vaccinated participants.

Pre- and postvaccination (2 weeks) serum dilutions at which 80% VN occurred in previously vaccinated participants. When 80% VN was not reached by the least diluted serum (1∶16), samples were defined as <16 (reciprocal serum dilution). VN = Virus neutralization.

Figure 4. Virus neutralizing capacity of YF-RNA negative and positive sera.

Comparison of reciprocal serum dilutions, of serum obtained 4 weeks after vaccination, at which 80% VN occurred between positive and negative YF-17D RNA detection by RT-PCR in primary vaccinated participants (N = 24). Bars represent the median reciprocal serum dilution. VN = Virus neutralization.